Purified Detomidine, Process of Preparing and Methods of Use

ABSTRACT

The present disclosure relates to a purified detomidine HCl pharmaceutical product and to methods of preparation, validation of pharmaceutically acceptable product and use thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of International ApplicationNo. PCT/IB2019/056160, filed Jul. 18, 2019, and claims the benefit ofU.S. Provisional Application No. 62/700,067, filed Jul. 18, 2018, theentireties of which are incorporated by reference herein.

TECHNICAL FIELD

The present disclosure relates to a purified detomidine HClpharmaceutical product and to methods of preparation, validation ofpharmaceutically acceptable product and use thereof.

BACKGROUND

Detomidine

Detomidine, 4-[(2,3-dimethylphenyl)methyl]-1H-Imidazole, is anα-2-andregenic agonist available under the brand name Equimidine® andDormosedan® for use as a veterinary sedative. Detomidine is notcurrently approved for human use.

Detomidine and related compounds, including its 3,4 dimethyl isomer,iso-detomidine (4-(3,4-Dimethylbenzyl)-1H-imidazole) were firstdescribed in U.S. Pat. No. 4,443,466. Both the '466 patent and the laterU.S. Pat. No. 4,584,383 describe the synthetic method of manufacturingdetomidine as being based on coupling of an imidazole moiety with1-Bromo-2,3-dimethyl benzene using a Grignard reaction. RU2448095describes an alternative route of synthesis of the molecule based oncoupling in presence of a Titanium catalyst. According to both the '383and '095 patents, detomidine is purified by crystallization of itshydrochloride salt from water. The chemical structures of detomidine HCland iso-detomidine are shown below:

Two solid state forms of detomidine HCl are known, the anhydrous andmonohydrate forms. Synthesis of the anhydrous form by crystallization ofthe monohydrate and further decomposition at elevated temperatures isdescribed in U.S. Pat. No. 7,728,147. Synthesis of the anhydrous formvia decomposition of the monohydrate in reduced pressure is described inLaine et al (1983). According to Veldre et al (2011), the anhydrous andmonohydrate forms of detomidine HCl can easily interconvert depending ontemperature and humidity.

The European Pharmacopeia 9.0 monograph (January 2014) describesdetomidine HCl for veterinary use. The monograph lists the establishedHPLC method for identification of detomidine and its impurities as usinga Symmetry C8, 5 μm, 4.6×150 mm column, with a mobile phase of Ammoniumphosphate buffer pH 7.9—65% and Acetonitrile—35% at a flow rate of 1.0mL/min and UV detection at 220 nm. That procedure is listed as recordingthree distinct impurities of detomidine:

Impurity A: (RS)-(2,3-dimethylphenyl)(1H-imidazol-4-yl)methanol

Impurity B: (RS)-(1-benzyl-1H-imidazol-5-yl)(2,3-dimethylphenyl)methanol

Impurity C: 4-[(2,3-dimethylcyclohexyl)methyl]-1H-imidazole

PCT/US18/012579 discloses topical formulations of detomidine and theiruses in treating pain.

Purified detomidine for use in human pharmaceutical formulations is notknown in the art.

SUMMARY OF THE DISCLOSURE

It has now been identified that commercially available detomidine HClproducts contain not only Impurity A(RS)-(2,3-dimethylphenyl)(1H-imidazol-4-yl)methanol), and potentiallyImpurities B(RS)-((1-benzyl-1H-imidazol-5-yl)(2,3-dimethylphenyl)methanol) and C(4-[(2,3-dimethylcyclohexyl)methyl]-1H-imidazole), but also significantquantities of iso-detomidine and/or iso-impurity A((RS)-(3,4-dimethylphenyl)(1H-imidazol-4-yl)methanol) and/or3-((1H-Imidazol-4-yl)methyl)-2-methylbenzaldehyde. Provided herein arethe compound, detomidine HCl substantially free of impurities, includingisomeric impurities of detomidine, compositions comprising same, aprocess for identifying the impurities and a novel processes for themanufacture of purified detomidine HCl.

The subject invention provides detomidine or a pharmaceuticallyacceptable salt thereof; the compound substantially free ofiso-detomidine and/or iso-impurity A:

and/or 3-((1H-Imidazol-4-yl)methyl)-2-methylbenzaldehyde (“aldehydeimpurity”):

3-((1H-Imidazol-4-yl)methyl)-2-methylbenzaldehyde (“Aldehyde Impurity”)

In some embodiments the detomidine or a pharmaceutically acceptable saltthereof, e.g. detomidine HCl, is substantially free of iso-detomidineand iso-impurity A((RS)-(3,4-dimethylphenyl)(1H-imidazol-4-yl)methanol).

In some embodiments the detomidine or a pharmaceutically acceptable saltthereof, e.g. detomidine HCl, is substantially free of iso-detomidineand 3-(1H-Imidazol-4-yl)methyl)-2-methylbenzaldehyde. In someembodiments the detomidine or a pharmaceutically acceptable saltthereof, e.g. detomidine HCl, is substantially free of iso-detomidine,iso-impurity A ((RS)-(3,4-dimethylphenyl)(1H-imidazol-4-yl)methanol) and3-((1H-Imidazol-4-yl)methyl)-2-methylbenzaldehyde.

In some embodiments, the pharmaceutically acceptable salt of detomidineis detomidine HCl. In some embodiments the detomidine HCl is themonohydrate form. In some embodiments the detomidine HCl is theanhydrate form.

In some embodiments, the total amount of impurities is not more than0.1% area, not more than 0.06% area, or not more than 0.02% area,relative to detomidine, based on HPLC, using UV detection at 220 nm. Insome embodiments, the total amount of impurities is not more than 0.06%area, relative to detomidine, based on HPLC, using UV detection at 220nm.

Further provided is a composition, optionally a pharmaceuticalcomposition, comprising detomidine or a pharmaceutically acceptable saltthereof, substantially free of iso-detomidine and/or iso-impurity Aand/or 3-((1H-Imidazol-4-yl)methyl)-2-methylbenzaldehyde. In someembodiments of the composition or pharmaceutical composition, thepharmaceutically acceptable salt of detomidine is detomidine HCl. Insome embodiments of the composition or pharmaceutical composition, thedetomidine HCl is the monohydrate form or the anhydrate form. In someembodiments of the composition or pharmaceutical composition, thedetomidine is substantially free of iso-detomidine. In some embodimentsof the composition or pharmaceutical composition, the detomidine issubstantially free of iso-detomidine and iso-impurity A((RS)-(3,4-dimethylphenyl)(1H-imidazol-4-yl)methanol). In someembodiments of the composition or pharmaceutical composition, thedetomidine is substantially free of iso-detomidine and3-((1H-Imidazol-4-yl)methyl)-2-methylbenzaldehyde. In some embodimentsof the composition or pharmaceutical composition, the detomidine issubstantially free of iso-detomidine, iso-impurity A((RS)-(3,4-dimethylphenyl)(1H-imidazol-4-yl)methanol) and3-(1H-Imidazol-4-yl)methyl)-2-methylbenzaldehyde.

In some embodiments the detomidine or a pharmaceutically acceptable saltthereof, e.g. detomidine HCl, is further substantially free ofiso-impurity A (((RS)-(3,4-dimethylphenyl)(1H-imidazol-4-yl)methanol)).In some embodiments the detomidine or a pharmaceutically acceptable saltthereof, e.g. detomidine HCl, is further substantially free of impurityA ((RS)-(2,3-dimethylphenyl)(1H-imidazol-4-yl)methanol). In someembodiments detomidine or a pharmaceutically acceptable salt thereof,e.g. detomidine HCl, is further substantially free of3-((1H-Imidazol-4-yl)methyl)-2-methylbenzaldehyde. In some embodiments,the detomidine or a pharmaceutically acceptable salt thereof, e.g.detomidine HCl, is further substantially free of impurity B((RS)-(1-benzyl-1H-imidazol-5-yl)(2,3-dimethylphenyl)methanol) and/orimpurity C (4-[(2,3-dimethylcyclohexyl)methyl]-1H-imidazole).

In some embodiments, the total amount of impurities in the detomidine ora pharmaceutically acceptable salt thereof, e.g. detomidine HCl, is notmore than 0.1% area, not more than 0.06% area, or not more than 0.02%area, relative to detomidine, based on HPLC, using UV detection at 220nm. In some embodiments, the total amount of impurities is not more than0.06% area, relative to detomidine, based on HPLC, using UV detection at220 nm.

The subject invention also provides a composition comprising

a) an amount of detomidine or a pharmaceutically acceptable saltthereof;

b) a vehicle; and optionally

c) an impurity which is iso-detomidine and/or iso-impurity A and/or3-((1H-Imidazol-4-yl)methyl)-2-methylbenzaldehyde,

wherein the impurity is present in an amount no more than 0.01% arearelative to the detomidine, based on HPLC, using UV detection at 220 nm.

The subject invention also provides a pharmaceutical compositioncomprising

a) an amount of detomidine or a pharmaceutically acceptable saltthereof;

b) at least one pharmaceutically acceptable carrier; and optionally

c) an impurity which is iso-detomidine and/or iso-impurity A and/or3-((1H-Imidazol-4-yl)methyl)-2-methylbenzaldehyde,

wherein the impurity is present in an amount no more than 0.01% arearelative to the detomidine, based on HPLC, using UV detection at 220 nm.

In some embodiments of the composition or pharmaceutical composition,the detomidine is detomidine HCl. In some embodiments the detomidine HClis the monohydrate form of detomidine HCl. In some embodiments thedetomidine HCl is the anhydrous form of detomidine HCl. In someembodiments the composition or pharmaceutical composition issubstantially free of iso-detomidine. In some embodiments thecomposition or pharmaceutical composition is substantially free ofiso-detomidine and iso-impurity A. In some embodiments, the compositionor pharmaceutical composition is substantially free of iso-detomidine,iso-impurity A and 3-((1H-Imidazol-4-yl)methyl)-2-methylbenzaldehyde. Insome embodiments, the composition or pharmaceutical composition issubstantially free of iso-impurity A and3-((1H-Imidazol-4-yl)methyl)-2-methylbenzaldehyde. In some embodiments,the composition or pharmaceutical composition is substantially free ofiso-detomidine and 3-((1H-Imidazol-4-yl)methyl)-2-methylbenzaldehyde.

In some embodiments of the composition or the pharmaceuticalcomposition, the detomidine or a pharmaceutically acceptable saltthereof, e.g. detomidine HCl, is further substantially free ofiso-impurity A (((RS)-(3,4-dimethylphenyl)(1H-imidazol-4-yl)methanol)).

In some embodiments the composition or the pharmaceutical composition,the detomidine or a pharmaceutically acceptable salt thereof, e.g.detomidine HCl, is further substantially free of impurity A((RS)-(2,3-dimethylphenyl)(1H-imidazol-4-yl)methanol).

In some embodiments of the composition or the pharmaceuticalcomposition, the detomidine or a pharmaceutically acceptable saltthereof, e.g. detomidine HCl, is further substantially free of3-((1H-Imidazol-4-yl)methyl)-2-methylbenzaldehyde.

In some embodiments of the composition or the pharmaceuticalcomposition, the detomidine or a pharmaceutically acceptable saltthereof, e.g. detomidine HCl, is further substantially free of impurityB ((RS)-(1-benzyl-1H-imidazol-5-yl)(2,3-dimethylphenyl)methanol) and/orimpurity C (4-[(2,3-dimethylcyclohexyl)methyl]-1H-imidazole).

The present invention further provides a process for the preparation ofa monohydrate form of detomidine HCl substantially free ofiso-detomidine comprising

-   -   a. crystallizing a monohydrate form of detomidine HCl from an        aqueous solution of an anhydrous form of detomidine HCl which        comprises iso-detomidine; wherein the crystallization takes        place by cooling the aqueous solution to a temperature of from        about 0° C. to 31° C., optionally in the presence of solid        detomidine base or detomidine HCl, until a slurry is formed, and    -   b. collecting the monohydrate form of detomidine HCl        substantially free of iso-detomidine.

Further provided is a process for the preparation of a monohydrate formof detomidine HCl substantially free of iso-detomidine comprising

-   -   a. treating an aqueous solution of an anhydrous form of        detomidine HCl which comprises iso-detomidine with active        carbon;    -   b. converting the detomidine HCl to detomidine base to form an        aqueous solution of detomidine base;    -   c. crystallizing the monohydrate form of detomidine HCl from the        aqueous solution of detomidine base by adding a sufficient        amount of HCl, wherein the crystallization takes place by        cooling the aqueous solution to between about 3° C. and 37° C.,        optionally in the presence of solid detomidine HCl, until a        slurry is formed, and    -   d. collecting the monohydrate form of detomidine HCl        substantially free of iso-detomidine.

In some embodiments of the processes, the HCl:detomidine base ratio(mole:mole) is about 1 to about 1.5, preferably about 1.5. In someembodiments, the water:detomidine (V/wt) HCl ratio is about 2-3.

In various embodiments, the crystallization of the monohydrate form ofdetomidine HCl from an aqueous solution occurs at a dissolutiontemperature of between about 35° C. and 50° C. In some embodiments, thecrystallization initiation temperature is about 30° C. to 45° C.

In some embodiments of the processes, the monohydrate form of detomidineHCl has a mean crystal size of 0.3 to 0.7 mm. In some embodiments, theshape of the crystals of the monohydrate form of detomidine HCl is rodlike and/or prism like. The monohydrate form of detomidine HCl has awater content of about 7.5% as determined by Karl Fisher analysis.

Further provided is the monohydrate form of detomidine HCl obtained bythe processes disclosed herein, and compositions and pharmaceuticalcompositions comprising same; and optionally a carrier.

Further provided is use of a pharmaceutical composition comprisingdetomidine or a pharmaceutically acceptable salt thereof, substantiallyfree of iso-detomidine; optionally further substantially free of theimpurity A ((RS)-(2,3-dimethylphenyl)(1H-imidazol-4-yl)methanol),3-((1H-Imidazol-4-yl)methyl)-2-methylbenzaldehyde, impurity B((RS)-(1-benzyl-1H-imidazol-5-yl)(2,3-dimethylphenyl)methanol) and/orimpurity C (4-[(2,3-dimethylcyclohexyl)methyl]-1H-imidazole).

Further provided is a method of treating a human subject in needthereof, comprising administering to the subject a pharmaceuticalcomposition comprising detomidine or a pharmaceutically acceptable saltthereof, substantially free of iso-detomidine; optionally furthersubstantially free of the impurity A((RS)-(2,3-dimethylphenyl)(1H-imidazol-4-yl)methanol),3-((1H-Imidazol-4-yl)methyl)-2-methylbenzaldehyde, impurity B((RS)-(1-benzyl-1H-imidazol-5-yl)(2,3-dimethylphenyl)methanol) and/orimpurity C (4-[(2,3-dimethylcyclohexyl)methyl]-1H-imidazole). In someembodiments the human subject is in need of an analgesic.

The subject invention yet further provides a process for producing avalidated batch of a drug substance containing detomidine or apharmaceutically acceptable salt thereof and at least onepharmaceutically acceptable carrier for distribution, the processcomprises:

a) obtaining a batch of the drug substance;

b) determining by apparatus the total amount of iso-detomidine and/oriso-impurity A and/or 3-((1H-Imidazol-4-yl)methyl)-2-methylbenzaldehydein a sample of the batch; and

c) validating the batch for distribution only if the sample of the batchis determined by weight of detomidine to contain less than 0.01% area ofiso-detomidine and/or iso-impurity A and/or3-((1H-Imidazol-4-yl)methyl)-2-methylbenzaldehyde relative to detomidinebased on HPLC, using UV detection at 220 nm.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: HPLC chromatogram showing impurity in sourced samples ofdetomidine HCl.

FIG. 2: HPLC chromatogram showing identification of the impurity peaks

FIG. 3 LC-MS/MS identifying one of the impurity peaks as iso-impurity A.

FIG. 4 HR-ESI-MS identifying one of the impurity peaks as3-((1H-Imidazol-4-yl)methyl)-2-methylbenzaldehyde.

FIG. 5 is a DVS isotherm plot showing hydration of detomidine free baseat 24.4° C.

FIG. 6 is a DVS isotherm plot showing hydration of detomidine HCl at24.7° C.

FIG. 7 a microphotograph of particle morphology of detomidine HClmonohydrate (sample 3).

FIG. 8 is a XRPD pattern of detomidine HCl monohydrate (sample 1).

FIG. 9 is a DSC thermogram of detomidine HCl monohydrate (sample 1).

FIG. 10 is a TGA thermogram of detomidine HCl monohydrate (sample 1).

FIG. 11 is a XRPD pattern of detomidine HCl monohydrate (sample 2).

FIG. 12 is a DSC thermogram of detomidine HCl monohydrate (sample 2).

FIG. 13 shows a TGA thermogram of anhydrous Detomidine HCl (sample 2).

FIG. 14 is a microphotograph of particle morphology of detomidine HClmonohydrate prepared according to the second procedure (Carbon treatmentand detomidine free base isolation, followed by crystallization).

FIG. 15 shows the 1H-NMR spectra of iso-detomidine.

FIG. 16 shows a XRPD pattern of detomidine free base (sample “70”)

FIG. 17 shows a DSC thermogram of detomidine free base.

FIG. 18 shows a TGA thermogram of detomidine free base.

DETAILED DESCRIPTION OF THE DISCLOSURE

The present invention is based, in part, on the identification ofimpurities present in detomidine preparations and methods ofsynthesizing and crystalizing detomidine to reduce the presence of theimpurities. The present invention further provides methods to preparepurified solid detomidine HCl for use as a drug substance.

Anhydrous detomidine HCl is available under the brand name, inter alia,Equimidine® and Dormosedan® as a veterinary sedative. Detomidine has notbeen approved for human use.

In the present disclosure the singular forms “a”, “an” and “the” includethe plural reference, and reference to a particular numerical valueincludes at least that particular value, unless the context clearlyindicates otherwise. For example, “the method” includes the broadestdefinition of the meaning of the phrase, which can be more than onemethod.

By any range disclosed herein, it is meant that all hundredth, tenth andinteger unit amounts within the range are specifically disclosed as partof the invention. Thus, for example, 0.01 mg to 50 mg means that 0.02,0.03 . . . 0.09; 0.1, 0.2 . . . 0.9; and 1, 2 . . . 49, 50 mg unitamounts are included as embodiments of this invention.

A characteristic of a compound refers to a quality that the compoundexhibits, as determined by for example, nuclear magnetic resonance (NMR)spectroscopy (nMS), mass spectroscopy (MS), infrared (IR), ultraviolet(UV) or fluorescence spectrophotometry, gas chromatography (GC), thinlayer chromatography (TLC), high performance liquid chromatography(HPLC), elemental analysis, microscopic analysis, Ames test, andincludes without limitation peaks, dissolution, stability, crystalshape, particle size, and any other quality that can be determined by ananalytical method. Once the characteristics of a compound are known, theinformation can be used to, for example, screen or test for the presenceof the compound in a sample and validate or reject a batch, for examplea pharmaceutical batch.

As used herein, “substantially free” refers to a compound or compositionhaving 0.01% area or less of a particular impurity or degradant, orhaving 0.1% area or less, 0.09% area or less, 0.08% area or less, 0.07%area or less, 0.06% area or less, 0.05% area or less, 0.04% area orless, 0.03% area or less, 0.02% area or less or 0.01% area or less, oftotal impurities or degradants, relative to detomidine, each asdetermined by HPLC, using UV detection at 220 nm. In preferredembodiments, the identification of impurities in the human detomidinedrug substance is identified by the exemplary HPLC method, as disclosedherein.

As used herein, a “pharmaceutically acceptable” carrier or excipient isone that is suitable for use with humans and/or animals without undueadverse side effects (such as toxicity, irritation, and allergicresponse) commensurate with a reasonable benefit/risk ratio.

As used herein, “drug substance” refers to the active ingredient in adrug product, which provides pharmacological activity, prior to itsincorporation into a drug product, in the treatment or prevention of asymptom or a disease, in a mammal, preferably a human.

As used herein, “drug product” refers to the dosage form containing thedrug substance as well as at least one pharmaceutically acceptablecarrier or excipient.

As used herein, a “composition” is distinct from a “pharmaceuticalcomposition”, in that it does not include a pharmaceutically acceptablecarrier or excipient. A composition as used herein is understood to bepresent in an inert environment. As used herein, a composition that is“free” of a chemical means that the composition contains, if at all, anamount of the chemical entity which cannot be avoided following anaffirmative action intended to eliminate the presence of the chemical inthe composition.

As used herein, “about” in the context of a numerical value or rangemeans within ±10% of the numerical value or range recited or claimed.

As used herein, to “treat” or “treating” encompasses, e.g., reducing asymptom, inducing inhibition, regression, or stasis of the disorderand/or disease.

“Administering to the human subject” means the giving of, dispensing of,or application of medicines, drugs, or remedies to a subject/patient torelieve, cure, or reduce the symptoms associated with a condition, e.g.,a pathological condition. The administration can be periodicadministration.

“Detomidine” refers to the compound,4-[(2,3-dimethylphenyl)methyl]-1H-imidazole, and to salts and hydrates,thereof. Detomidine is identified by CAS 76631-46-4 and detomidine HClby CAS 90038-01-0.

Detomidine can be administered in admixture with suitable pharmaceuticaldiluents, extenders, excipients, or carriers (collectively referred toherein as a pharmaceutically acceptable carrier) suitably selected withrespect to the intended form of administration and as consistent withconventional pharmaceutical practices. The unit is preferably in a formsuitable for topical administration. Detomidine can be administeredalone but is generally mixed with a pharmaceutically acceptable carrier.

General techniques and compositions for making dosage forms useful inthe present invention are known to one of skill in the art.

This invention will be better understood by reference to theexperimental details which follow, but those skilled in the art willreadily appreciate that the specific experiments detailed are onlyillustrative of the invention as described more fully in the claimswhich follow thereafter.

ASPECTS

Aspect 1. Detomidine or a pharmaceutically acceptable salt thereof, thatis substantially free of the compound that has a mass-to-charge ratio of201 and elutes at RRT 0.38 when subjected to high performance liquidchromatography (HPLC);

-   -   wherein the HPLC method comprises        -   a SunFire C8 column, 100 Å, 3.5 μm, 4.6×150 mm,        -   an initial mobile phase that is 70% Ammonium Phosphate            buffer solution, pH 7.9, and 30% Acetonitrile,        -   a flow rate of 1.0 mL/min, and        -   UV detection at 220 nm.

Aspect 2. The detomidine of claim 1, wherein the pharmaceuticallyacceptable salt of detomidine is detomidine HCl.

Aspect 3. The detomidine of claim 2, wherein the detomidine HCl is themonohydrate form.

Aspect 4. The detomidine of claim 2, wherein the detomidine HCl is theanhydrous form.

Aspect 5. The detomidine any one of claims 1-4, wherein the total amountof impurities is not more than 0.1% area, not more than 0.06% area, ornot more than 0.02% area, based on HPLC.

Aspect 6. The detomidine of any one of claims 1-5, wherein the totalamount of impurities is not more than 0.06% area, based on HPLC.

Aspect 7. The detomidine of any one of claims 1-6, wherein thedetomidine or a pharmaceutically acceptable salt thereof is furthersubstantially free of iso-impurity A(((RS)-(3,4-dimethylphenyl)(1H-imidazol-4-yl)methanol)).

Aspect 8. The detomidine of any one of claims 1-7, wherein thedetomidine or a pharmaceutically acceptable salt thereof is furthersubstantially free of impurity A((RS)-(2,3-dimethylphenyl)(1H-imidazol-4-yl)methanol).

Aspect 9. The detomidine of any one of claims 1-8, wherein thedetomidine or a pharmaceutically acceptable salt thereof is furthersubstantially free of impurity B((RS)-(1-benzyl-1H-imidazol-5-yl)(2,3-dimethylphenyl)methanol) and/orimpurity C (4-[(2,3-dimethylcyclohexyl)methyl]-1H-imidazole).

Aspect 10. A composition comprising the detomidine of any one of claims1-9, and a vehicle.

Aspect 11. A pharmaceutical composition comprising detomidine or apharmaceutically acceptable salt thereof substantially free of thecompound that has a mass-to-charge ratio of 201 and elutes at RRT 0.38when subjected to high performance liquid chromatography (HPLC); and apharmaceutically acceptable carrier;

-   -   wherein the HPLC method comprises        -   a SunFire C8 column, 100 Å, 3.5 μm, 4.6×150 mm,        -   an initial mobile phase that is 70% Ammonium Phosphate            buffer solution, pH 7.9, and 30% Acetonitrile,        -   a flow rate of 1.0 mL/min, and        -   UV detection at 220 nm.

Aspect 12. The pharmaceutical composition of claim 11, wherein thepharmaceutically acceptable salt of detomidine is detomidine HCl.

Aspect 13. The pharmaceutical composition of claim 12, wherein thedetomidine HCl is the monohydrate form.

Aspect 14. The pharmaceutical composition of claim 12, wherein thedetomidine HCl is the anhydrous form.

Aspect 15. The pharmaceutical composition of any one of claims 11-14,wherein the total amount of impurities is not more than 0.1% area, notmore than 0.06% area, or not more than 0.02% area, based on HPLC.

Aspect 16. The pharmaceutical composition of any one of claims 11-14,wherein the total amount of impurities is not more than 0.06% area,based on HPLC.

Aspect 17. The pharmaceutical composition of any one of claims 11-16,further substantially free of iso-impurity A(((RS)-(3,4-dimethylphenyl)(1H-imidazol-4-yl)methanol)).

Aspect 18. The pharmaceutical composition of any one of claims 10-17,further substantially free of impurity A((RS)-(2,3-dimethylphenyl)(1H-imidazol-4-yl)methanol).

Aspect 19. The pharmaceutical composition of any one of claims 10-18,further substantially free of impurity B((RS)-(1-benzyl-1H-imidazol-5-yl)(2,3-dimethylphenyl)methanol) and/orimpurity C (4-[(2,3-dimethylcyclohexyl)methyl]-1H-imidazole).

Aspect 20. A process for the preparation of a monohydrate form ofdetomidine HCl substantially free of iso-detomidine comprising

-   -   a. crystallizing a monohydrate form of detomidine HCl from an        aqueous solution of an anhydrous form of detomidine HCl which        comprises iso-detomidine; wherein the crystallization takes        place by cooling the aqueous solution to a temperature of from        about 0° C. to 31° C., optionally in the presence of solid        detomidine base or detomidine HCl, until a slurry is formed, and    -   b. collecting the monohydrate form of detomidine HCl        substantially free of iso-detomidine.

Aspect 21. A process for the preparation of a monohydrate form ofdetomidine HCl substantially free of iso-detomidine comprising

-   -   a. treating an aqueous solution of an anhydrous form of        detomidine HCl which comprises iso-detomidine with active        carbon;    -   b. converting the detomidine HCl to detomidine base to form an        aqueous solution of detomidine base;    -   c. crystallizing the monohydrate form of detomidine HCl from the        aqueous solution of detomidine base by adding a sufficient        amount of HCl, wherein the crystallization takes place by        cooling the aqueous solution to between about 3° C. and 37° C.,        optionally in the presence of solid detomidine HCl, until a        slurry is formed, and    -   d. collecting the monohydrate form of detomidine HCl        substantially free of iso-detomidine.

Aspect 22. The process of claim 20 or 21, wherein the HCl:detomidinebase ratio (mole:mole) is about 1 to about 1.5.

Aspect 23. The process of claim 22, wherein the HCl:detomidine baseratio (mole:mole) is about 1.5.

Aspect 24. The process of any one of claims 20-23, wherein thewater:detomidine (V/wt) HCl ratio is about 2-3.

Aspect 25. The process of any one of claims 20-24, wherein thecrystallization of the monohydrate form of detomidine HCl from anaqueous solution occurs at a dissolution temperature of between about35° C.-50° C.

Aspect 26. The process of any one of claims 20-25, wherein thecrystallization initiation temperature is about 30° C.-45° C.

Aspect 27. The process of any one of claims 20-26, wherein themonohydrate form of detomidine HCl has a mean crystal size of 0.3 to 0.7mm.

Aspect 28. The process of claim 27, wherein the shape of the crystals ofthe monohydrate form of detomidine HCl is rod like and/or prism like.

Aspect 29. The process of any of claims 20-28 wherein the monohydrateform of detomidine HCl has a water content of about 7.5% as determinedby Karl Fisher analysis.

Aspect 30. The monohydrate form of detomidine HCl obtained by a processof any one of claims 20-29.

Aspect 31. A composition comprising the monohydrate form of detomidineHCl obtained by a process of any one of claims 20-29; and a vehicle.

Aspect 32. A pharmaceutical composition comprising the monohydrate formof detomidine HCl obtained by a process of any one of claims 20-29; anda pharmaceutically acceptable carrier.

Aspect 33. A method of treating a human subject in need thereof,comprising administering to the human subject the pharmaceuticalcomposition of any one of claims 11-19 and 32.

Aspect 34. The method of claim 33, wherein the human subject is in needof an analgesic.

Aspect 35. A process for validating a batch of a monohydrate form ofdetomidine HCl drug substance, comprising

-   -   a. determining the amount of iso-detomidine in a sample of the        batch, and    -   b. validating the batch for distribution only if the sample of        the batch contains not more than 0.01% area of iso-detomidine        and/or iso-impurity A relative to detomidine.

Aspect 36. The detomidine of claim 1, which is detomidine free base.

Aspect 37. The detomidine free base of claim 36, having 2 theta valuescomprising at least one of the values as shown in Table 16, herein.

Aspect 38. Detomidine, or a pharmaceutically acceptable salt thereof,having 0.01% area or less, relative to detomidine, of the compound thathas a mass-to-charge ratio of 201 and elutes at RRT 0.38 when subjectedto high performance liquid chromatography (HPLC);

-   -   wherein the HPLC method comprises        -   a SunFire C8 column, 100 Å, 3.5 μm, 4.6×150 mm,        -   an initial mobile phase that is 70% Ammonium Phosphate            buffer solution, pH 7.9, and 30% Acetonitrile,        -   a flow rate of 1.0 mL/min, and        -   UV detection at 220 nm.

EXAMPLES Example 1: Elemental Analysis of Impurities Found inCommercially Available Anhydrous Detomidine HCl Example 1a

Anhydrous detomidine HCl was sourced from two commercial API suppliers.Properties of the commercial batches, GMP1, GMP2 and GMP3, are presentedbelow.

Elemental impurity analysis was performed by inductively coupled plasmamass spectrometry (ICP-MS) on four different batches of sourcedanhydrate. The results of the analysis are found in Table 1.

TABLE 1 Elemental impurities in anhydrous detomidine HCl Table 1 BatchNon-GMP, GMP1, GMP2, GMP3, Off-white white white white Element^(i))Content, mg/kg API Al 1.4 <0.5 <0.5 <0.5 B 3.08 0.43 0.39 0.14 Ca 16328.6 27.3 19.5 Cr 0.8 <0.5 <0.5 0.7 Cu 1.0 <0.2 <0.2 <0.2 Fe 5.62 0.210.24 0.11 Pd <0.2 0.9 3.3 5.3 Mg 5.9 <1 <1 <1 Mn 2.0 <0.2 <0.2 <0.2 Ni<0.5 <0.5 <0.5 0.7 Si 61.7 <15 <15 <15 S 201.6 <15 <15 <15 Zn 17.6 1.82.8 1.2 ^(i))Elements having levels L.T. 0.5 mg/kg (Ti, As, Hg, Pb, Mo,Pt, etc) are not presented in the table

The screening of elemental impurities shows that the GMP productscontained significant levels of Pd (0.9-5.3 mg/kg). Pd is understood tobe a catalyst used in the synthesis of detomidine (e.g., inreduction/hydrogenation methods).

Example 1b: Characterization of Commercially Sourced Material

Samples of the anhydrous detomidine products described in Table 1 wereanalyzed for water content and characterized by microscope, XRPD andthermal analyses. The results are summarized in Table 2.

TABLE 2 Characterization of commercial anhydrous detomidine HCl Form bym.p. by DSC LOD by TGA Batch XRPD ° C. % Non-GMP, Off- Mixture^(a) Twopeaks at 95° 2.7 white and 160° GMP1, white Mixture^(a) Two peaks at95.5° 0.7 and 157° GMP2, white Mixture^(a) A tiny peak at 95° 0.3 andpeak at 159.6° GMP3, white Mixture^(a) Two peaks at 95° 0.6 and 159°^(a)Anhydrous + monohydrate

The values presented in Table 2 demonstrate that the commercial samplesof detomidine HCl labeled as anhydrous contain some amount ofmonohydrate and this amount varied depending on storage conditions andpackaging.

Example 2: Stability Assessment of Anhydrate and Monohydrate Forms ofDetomidine Base and Detomidine HCl

Pure forms of crystalline free base, and HCl salt (both monohydrate andanhydrate) were prepared from commercially sourced anhydrous detomidineHCl as outlined in Table 3, and characterized using XRPD and thermalanalysis. The solids were crystallized from aqueous solutions and thendried under different conditions. The crystallization and dryingconditions are summarized in Table 3.

TABLE 3 Preparation of detomidine HCl crystalline forms Dryingconditions Sample P; Time; Yield No. Preparation procedure T ° C. mbarhrs % 1 Re-crystallization of anhydrous RT 20 22 84.5 detomidinehydrochloride from 2.88 vol. water 2 Re-crystallization of anhydrous 9030-40 25 84 detomidine hydrochloride from 2.88 vol. water 3 Drying undervacuum 90 30-40 17 100 4 Splitting of detomidine hydrochloride 45 30-4013 85.2 with NaOH in water, precipitation and isolation of detomidinefree base. Reaction of detomidine free base with HCl 1.05 eq. in 2.80vol. water 5 Carbon treatment of detomidine 45 30-40 15.5 84.5hydrochloride in water, splitting with NaOH, precipitation and isolationof detomidine free base. Reaction of detomidine free base with HCl 1.05eq. in 2.80 vol. water

The properties of the solids crystallized according to Table 3 aredescribed in Table 4.

TABLE 4 Properties of Detomidine HCl crystalline forms m.p. LOD open byWater Particle Sample capillary TGA DSC by cKF habit, by No. Color ° C.XRPD % ° C. % microscope 1 Off- 158.8-159.8 Monohydrate 7.66 Two melting7.36 Large white peaks 94°, regular 140° prisms 2 Off- 159.8-160.6Anhydrous 0.04 Melting at N.A. Small white 160° irregular particles 3Off- 158.6-160.1 Anhydrous 0.3  Melting at N.A. Small white 160°irregular particles 4 Off- N.A. Monohydrate 7.16 Two melting N.A. Largewhite peaks 94°, regular 157° prisms and rods 5 White N.A. MonohydrateN.A. N.A. 7.46 Large regular prisms and rods

These results demonstrate that crystallization from 2.8-2.9 volumes ofwater is effective for isolation and purification of the detomidine HClmonohydrate drug substance. Drying of the monohydrate under mildconditions (20-40 mbar and temperatures from at least ambient to about45° C.) provided pure monohydrate without traces of the anhydrous form.

The same monohydrate dried at elevated temperature (30-40 mbar 90° C.)converted completely into the anhydrous form. The vacuum dried,hermetically closed anhydrate did not absorb water from the atmosphereand did not convert into the monohydrate. After exposure to atmosphericair, however, the anhydrate absorbed water and converted to a mixture ofanhydrate and monohydrate.

Melting points (m.p.) of the intermediate detomidine free base andhydrochloride of Sample 5 measured in open capillary corresponded withthe published literature and the DSC data and are presented in Table 5.In order to evaluate effect of humidity on different forms ofdetomidine, a hydration study was performed. Samples of detomidine freebase and hydrochloride salt were subjected to DVS analysis. Theseobservations are in accordance with the DVS results shown in FIGS. 5 and6, for detomidine free base and detomidine HCl, respectively.

TABLE 5 Composition and properties of known solid forms of detomidinem.p., open Content, % wt. capillary Solid form MW Base HCl Water ° C.Free base 186.2 100 0 0 118-119 (114- 116)^(a) Hydrochloride 222.7 83.616.4 0 158-160 anhydrous Hydrochloride 240.7 77.3 15.2 7.5 159-160 (160-monohydrate 161)^(a) ^(a)literature data

The free base was found to be crystalline and insoluble in water but itreacted readily with aqueous HCl giving soluble detomidinehydrochloride.

Crystallization from water provided effective purification of thedetomidine HCl and formation of large regular crystals. Anhydrousdetomidine hydrochloride appeared as small irregular particles whereasthe possibility to control particle size distribution by crystallizationparameters existed for the monohydrate.

The detomidine free base was found to be non-hygroscopic, but also ableto absorb more than 1% of water at relative humidity (RH)>50%. Anincrease of humidity from RH 70% to RH>90% did not lead to absorption ofadditional water to monohydrate. During the dehydration cycle, themonohydrate began to lose water at RH˜10% and converted into theanhydrate at RH=0%. Anhydrate did not absorb water at RH<30% andtransformed completely to into the monohydrate at RH between 30% and50%.

Four cycles of hydration-dehydration demonstrated good reproducibilityof anhydrate-monohydrate interconversion.

An anhydrous detomidine HCl of Sample 2 was shown to absorb water to alevel of cKF 7.7% which corresponds well to the theoretical amount ofwater in the monohydrate form (Table 5). The hydration profile ofdetomidine hydrochloride showed that the monohydrate is stable in a widerange of humidity between 10% and >90% RH. At the same time, theanhydrous form is not stable in atmospheric air and absorbs water atRH=30-50%.

This data demonstrates that the anhydrous form is challenging in theaspects of water content and solid form stability and that detomidineHCl monohydrate is more suitable for pharmaceutical development.

Example 3: Impurity Analysis of Commercially Sourced Detomidine HCl

Using the established Pharmacopeia HPLC protocol (Symmetry C8, 5 μm,4.6×150 mm column, with a mobile phase of 65% Ammonium phosphate bufferpH 7.9 and 35% Acetonitrile at a flow rate of 1.0 mL/min and UVdetection at 220 nm), sourced samples of detomidine HCl were assayed forimpurities. As shown in FIG. 1, a previously unreported peak wasidentified, which partially overlapped with that of detomidine. ByLC-MS/MS analysis, this impurity was shown to have the same molecularweight as detomidine.

The established Pharmacopeia HPLC protocol did not separate thedetomidine from the impurity. Therefore, for further identification ofthe elusive impurity, new HPLC protocols for assaying detomidine HClwere developed. One protocol (“HPLC Protocol A”) comprised using aSunFire C8 column, 100 Å, 3.5 μm, 4.6×150 mm column with an initialmobile phase of 70% Ammonium Phosphate buffer solution, pH 7.9 and 30%Acetonitrile, at a flow rate of 1.0 mL/min and UV detection at 220 nm.To remove late eluting peaks, the flush gradient shown in Table 6 wasapplied after each run. This HPLC protocol allowed for a resolutionfactor of 3.9 between detomidine and the unidentified impurity. Thequantitation level (QL) for impurities and degradation products is0.025%. The detection level (DL) for impurities and degradation productsis 0.01%.

TABLE 6 Flush gradient for HPLC protocol % Ammonium Phosphate Time, minbuffer solution % Acetonitrile 0 70 30 25 70 30 27 30 70 32 30 70 33 7030 35 70 30

Given its molecular weight, it was hypothesized that the impurity wasiso-detomidine.

A solution of 100 μg/ml detomidine HCl and about 1 μg/mL (about 1% ofthe working concentration) of detomidine impurity A and iso-detomidinewere prepared and assayed using the new HPLC protocol (HPLC Protocol A),disclosed hereinabove. FIG. 2 is a chromatogram showing that thepreviously unreported peak is confirmed as being iso-detomidine.

The analysis of commercially sourced detomidine HCl revealed asignificant additional impurity. Table 7 provides levels of the variousdetomidine impurities in different commercial batches. In all batches,total impurities were observed at levels of >0.1% area.

TABLE 7 Impurity levels (% area) in commercial batches of detomidine.impurity A iso- Total Form Production (RRT = 0.33) RRT = 0.38 detomidineImpurities Anhydrous Non-GMP 0.07 ND 0.21 0.32 Anhydrous Non-GMP 0.15 ND0.02 0.19 Monohydrate + GMP 0.03 0.02 0.02 0.11 Anhydrous (15:85)Monohydrate GMP 0.04 0.17 0.01 0.3  Monohydrate¹ GMP 0.01 0.01 ND 0.04¹provided by commercial supplier after undergoing the recrystallizationprocess of Example 5, provided by inventors.

Further analysis of the peak at RRT=0.38 showed that it actuallyconsisted of 2 separate, overlapping peaks. As shown in FIG. 3, LC-MS/MSanalysis confirmed one of these peaks as iso-impurity A. After isolationand purification by preparative HPLC, further analysis, using ¹H and ¹³CNMR, LC-MS and HR-ESI-MS and as shown in FIG. 4, the obtained materialidentified the second peak as3-((1H-Imidazol-4-yl)methyl)-2-methylbenzaldehyde.

Example 4: Optimization of the Crystallization Method of Detomidine HClMonohydrate from Commercial Batches of Anhydrous Detomidine HCl

Crystallization experiments on 25, 65, and 770 gram scale were performedin 100 ml, 500 ml and 3 liter jacketed glass reactors, respectively,equipped with CBT (curved blade turbine) mechanical stirrers,circulating oil bath, thermocouples, and condensers. Stirrer speed inall experiments was between 300-600 rpm. Variable process parameterswere: amounts of HCl, solvent ratio, cooling time/rate, seeding and cakewash. The parameters and the variation ranges were chosen according toproduction conditions. The crystallization parameters are summarized inTable 8.

TABLE 8 Crystallization parameters Temperature Batch HCl:base Water:DetHCl Solid Crystallization End of Cooling Cake size ratio ratiodissolution initiation cooling time wash w/ Yield Batch gram Mole:moleV/wt ° C. hrs water % 82 65 1.5 2.80 45 38  3 1.5 Yes 91.4 83 65 1.52.80 45 42^(a) 3 8   Yes 93.5 84 25 1.0 2.80 Re-slurry ofanhydrate:monohydrate No 60.8 mixture (15:85) at 24° C.^(b) 85 26 1.02.80 Re-slurry of anhydrate at 24° C.^(b) No 65.6 86 26 1.5 2.80 44.643^(a) 4 4.5 No 95.4 87 26 1.5 2.80 46.6 43^(c) 2.5 4.5 No 95.8 88 261.5 2.80 45 39^(c) 3 5.5 No 94.9 89 26 1.0 2.10 48.7 35  3 5.5 No 86.490 770 1.5 2.80 46.6 45^(a) 1.5 5.5 + 12^(d) No 94.6 (sample 3)  91^(e)26.5 1.0 2.80 47 42^(a) 3 5.5 Yes 75.9 ^(a)Seeding with detomidine HClmonohydrate ^(b)Time 24 hrs ^(c)Seeding with anhydrous detomidine HCl^(d)5.5 hrs cooling and overnight stirring at 1-3° C. ^(e)Spiked with 2%iso-detomidine

The drying parameters and solid properties of batches shown in Table 8are described in Table 9.

TABLE 9 Drying parameters and solid properties of detomidine monohydratecrystals Drying LOD by H₂O by PSD Time XRPD TGA CKF D(0.1) D(0.5) D(0.9)D(1.0) Crystal Batch T ° C. P mbar Hrs Form^(ii)) % % μm μm μm μm habit^(i)) 82 30 30-40 16.5 M 6.9 7.7 174 451 982 2100 Rods 83 30 30-40 15 M7.3 7.9 442 726 1180 2100 Prisms, “rounded” 84 30 20-35 20 M 8.0 7.6 173415 840 1620 Rods and prisms 85 30 20-35 20 M 7.7 7.3 35.9 87.3 170 309Irregular aggregated particles 86 30 25-28 19 M 7.7 7.4 296 536 842 1260Rods and prisms 87 30 25-28 19 M 7.6 7.2 193 340 551 859 Clusters ofsmall prisms 88 30 25-30 17 M 7.7 7.4 133 287 438 661 Rods 89 30 25-3017 M 7.7 7.5 284 556 961 1630 Rods and prisms 90 30-40 18-35 20 M 7.67.4 246 434 645 898 Prisms, “rounded” 91 35 18-21 16 N.A. N.A. N.A. 423743 1270 2380 Prisms ^(i)) microscopic observation: Rods—aspect ratio >2; prisms—aspect ratio < 2 ^(ii))M = monohydrate

The data presented in Tables 8 and 9 demonstrate that crystallizationfrom water and drying under technical vacuum gives pure detomidine HClmonohydrate without traces of the detomidine HCl anhydrous form.Variations of HCl excess from 0 to 0.5 mole/mole base, cooling time from1.5 to 24 hours and drying time from 15 to 33 hours appear to have noeffect on the obtained properties of the solid form. All crystallizationproducts appeared as pure detomidine HCl monohydrate.

The crystallization initiation method also had no effect on crystallineform. The batches seeded with anhydrous material gave the samemonohydrate as batches seeded with monohydrate and batches whichcrystallized spontaneously.

Contact with water for 24 hrs completely converted the anhydrous forminto the monohydrate, even without complete dissolution (re-slurry).

Crystallization of the monohydrate from water gave large clearcrystalline particles with a mean crystal size 0.3-0.7 mm, with somecrystals larger than 2 mm in size. The shape of the crystals wasrod-like or prism-like, if the aspect ratio of the crystals was <2 thecrystals were reported in Table 8 as prisms.

A ratio of HCl to base within the range 1.0-1.5 mole:mole and water tosolid ratio within the range 2.1-2.8 V/wt were found to have nosignificant effect on the particle size distribution (PSD). However, aratio of HCl to base of about 1.5 were found to increase yields ofhighly pure detomidine HCl monohydrate from under 90% (60.8%-86.4%) toover 90% (91.4%-95.9%). Seeding also appeared to have no significanteffect on PSD.

The cooling rate was found to have a weak effect on PSD. There was noeffect observed for cooling over a time range between 1.5 and 5.5 hrs(mean cooling rate 0.10-0.31° C./min).

Slurry-to-slurry recrystallization of anhydrous material resulted in astrong reduction in particle size with the d(0.5) decreasing from300-500μ to 87μ. These crystals were found irregular with no signs ofprism-like or rod-like habit. In contrast, the re-slurry procedureapplied to a mixture of anhydrate and monohydrate (15:85) gave a mixtureof rod and prism-like crystals with d(0.5)=415μ.

Batch size was found to have no significant effect on crystal size andshape. After scaling up from a 26 g batch in 100 ml reactor to 770 g ina 3 liter reactor, the PSD was very similar to that of small scalebatches.

Prolonged cooling resulted in a “rounded” form of crystals. This effectwas observed in two experiments, as seen in the microscopic photographin FIG. 7. In the first experiment the crystallizing suspension wascooled for 8 hrs, and in the second one it was stirred at lowtemperature for 12 hrs (batches 83 and 90 in Tables 8 and 9).

Under the conditions described, cooling had a strong effect on theprocess yield. Two re-slurry experiments were performed at the samewater volume ratio as most of experiments (2.80 V/wt) but these twobatches were not cooled and filtered at 24° C. In these experiments theyield dropped from 86% to 60-65% (batches 84, 85 in Tables 8 and 9).

Acceptable yields were obtained in cooled batches within the solventvolume ratio range 2.1-2.8 V/wt with the cooling temperature betweenabout 1.5° C.-4° C.

An increase of HCl to base molar ratio from 1 to 1.5 was found to raisethe yield from 86% to 95%. Cake wash reduced the yield by 2-3%.Re-crystallization in presence of 2% iso-detomidine reduced the yieldfrom 84-85% to 76%. The purity of the samples prepared according tomethods disclosed in Tables 8 and 9, determined using the optimized HPLCmethod, are presented in Table 10.

TABLE 10 After crystallization Before Batch crystallization 83 84 85 8687 88 89 Color Non GMP, White White White White White White White WhiteImpurities by HPLC, % area RRT = 0.20- ND ND ND ND ND ND ND ND 0.21%area Impurity A 0.15 0.03 0.04 0.05 0.04 0.04 0.04 0.04 (RRT = 0.33%area) RRT = 0.43% 0.01 ND ND ND ND ND ND ND area RRT = 0.61% ND 0.01 NDND ND ND ND ND area iso-detomidine 0.02 ND ND ND ND ND ND ND (RRT =1.14% area) Total Impurities 0.19 0.04 0.04 0.05 0.04 0.04 0.04 0.04

Example 5: Purification of Organic Impurities from Detomidine HClMonohydrate

Two potential procedures for purification of organic impurities fromsourced monohydrate were compared. The first attempted procedure was bydirect re-crystallization of detomidine HCl from 2.88 volumes of water,while the second included carbon treatment and precipitation ofdetomidine free base followed by the free base being reacted with HCland crystallized as monohydrate. Both procedures used the same non-GMP,off white anhydrous detomidine HCl starting material which hadpreviously been shown in Table 7 to contain 0.21% of iso-detomidine and0.07% of Impurity A. All the re-crystallized materials were found tohave practically the same purity level. The direct re-crystallizationprocedure was found to provide a product with a high yield and purityand at the same time provides a practical and scalable crystallizationprocess which could be controlled by process parameters such as seedingand cooling rate.

Example 5a: Direct Recrystallization

Anhydrous detomidine HCl (4.5 g) was introduced to a round-bottom flaskwith a magnetic stirrer and thermometer. Deionized water (13 ml) wasthen added and the mixture stirred and heated in a water bath. At 39°C., the complete dissolution of solids was observed, providing a clearyellow solution with a pH=4.

The batch was gradually cooled by stirring. At 31° C., intensivecrystallization was observed. The resulting slurry was cooled in anice-water bath for 20 min and filtered. Flask and cake were then washedwith 2 ml of cold deionized water and 3.97 g of a white to cream coloredsolid was collected.

2.03 g of the material was dried in a vacuum desiccator at ambienttemperature and 20 mbar to a constant weight over 23 hrs producing a drymonohydrate −1.96 g off-white crystalline solid (sample 1).

An additional 1.91 g of the material was dried in a vacuum oven at 90°C. under house vacuum to a constant weight over about 24.5 hrs producinga dry anhydrate, 1.68 g off-white solid (sample 2)

The two samples were subjected to physical characterization and purityanalysis by HPLC. The XRPD spectra and DSC and TGA thermograms of sample1 are presented in FIGS. 8-10 and of sample 2 are presented in FIGS.11-13, respectively.

As shown in Table 11, direct re-crystallization resulted in theeffective purification from all organic impurities, but was noteffective for color. The content of iso-detomidine and of Impurity A wasreduced to a level below the QL, but the off white color remained afterre-crystallization.

TABLE 11 properties following direct recrystallization (sample 1) BeforeAfter re-crystallization re-crystallization Color Off-white Off-whiteImpurities by HPLC, % area RRT = 0.20-0.21% area 0.06 0.02 Impurity A(RRT = 0.33) 0.07 0.01¹ RRT = 0.48% area² 0.01 ND iso-detomidine (RRT =1.14) 0.21 0.01¹ Total Impurities 0.32 0.02 ¹below the QL ²system peak

Example 5b(i): Carbon Treatment and Detomidine Free Base Isolation

Anhydrous detomidine HCl (70.3 g) and deionized water (220 ml) wereintroduced to a 0.5 liter jacketed glass reactor equipped with amechanical stirrer, thermocoupler and a circulating oil bath for heatingand cooling.

The mixture was heated while stirring. At 40° C., complete dissolutionwas observed. Active carbon (CXV type, 5.2 g) was added to the clearyellow solution and the batch stirred at 45° C. for 50 minutes.Following this, the batch was filtered on through paper filter onBüchner funnel, reactor and filter washed with deionized water (20 ml).

The slightly yellowish clear filtrate was reintroduced to the 0.5 literreactor, stirred and 40% NaOH solution was added at 40° C. After 10 mlNaOH solution was added, a pH of 7 was reached and precipitation began.An additional 13 ml of NaOH was added over 1 hour at 42-52° C. andintensive stirring (400-450 rpm) performed. The mixture at the end ofthe addition of NaOH had a pH of 13.

The batch was stirred at 33-35° C. overnight then cooled to 16° C. over4 hours and stirred at this temperature for an additional hour. Theresultant solid was filtered on Büchner filter, reactor and cake washedwith two portions of deionized water (2×200 ml). The wet solid (86 g)was dried in a vacuum oven at 45° C. to constant weight to produce a dryproduct (53.2 g, Yield 90.7%)—white powder, m.p.=118.6-119.2

The dry detomidine base was analyzed for purity by HPLC, the resultspresented in Table 12.

TABLE 12 Properties of detomidine base (intermediate in sample 2) BeforeFree base purification (dry) Color Off-white White Impurities by HPLC, %area RRT = 0.20-0.21% area 0.06 0.05 Impurity A (RRT = 0.33) 0.07 0.02RRT = 0.48% area¹ 0.01 0.01 iso-detomidine 0.21 0.13 (RRT = 1.14% area)Total Impurities 0.31 0.22 ¹system peak

Example 5b(ii): Monohydrate Crystallization from Detomidine Base

The dry detomidine free base (53.0 g) from Example 5b(i) was introducedtogether with 37% HCl (29.7 g) and deionized water (159 g) into a 0.5liter jacketed glass reactor equipped with a mechanical stirrer, athermocoupler and a circulating oil bath for heating and cooling. Thebatch was stirred and heated to 45° C., at 37° C. complete dissolutionof solid was observed. The clear solution had a pH of 1. The solutionwas cooled gradually to 37° C. and seeded with detomidine HClmonohydrate and cooled gradually to 3° C. over 4 hours, and then thebatch was stirred for 45 minutes at this temperature.

The solid was filtered on Büchner filter, reactor and cake washed withcold deionized water (80 ml). The wet solid (61.9 g) was dried in vacuumoven for 16 hours at 45° C. to produce a dry product (57.8 g, Yield84.3%)—white crystalline powder (sample 2)

The dry detomidine HCl monohydrate was analyzed for water by CKF(H₂O=7.46%) and for purity by HPLC with the results presented in Table13. Microscopic observation for particle morphology (regular prisms) wasperformed and the microscopic photograph is shown in FIG. 14.

TABLE 13 Properties of detomidine HCl (sample 2) Before Monohydrateafter purification crystallization Color Off-white White Impurities byHPLC, % area RRT = 0.20-0.21% area 0.06 ND Impurity A (RRT = 0.33% area)0.07 ND RRT = 0.48% area¹ 0.01 ND iso-detomidine (RRT = 1.14% 0.21 NDarea) Total Impurities 0.31 ND ¹system peak

Example 5c: Re-Crystallization of Detomidine HCl to Monohydrate, BenchScale Experiment

Anhydrous detomidine HCl (754.6 g) 37% HCl (116.0 g) and deionized water(2008 g) were introduced to a 3 liter glass jacketed reactor equippedwith a mechanical stirrer, two baffles, a thermocoupler and acirculating oil bath for heating and cooling. The batch was stirred andheated to 52° C., at 47° C. complete dissolution was observed and theclear solution was found to have a pH of 0-0.5.

The solution was cooled gradually and at 45° C. seeded with detomidineHCl monohydrate (0.5 g). Crystallization initiation was observed at 43°C. and the batch was then cooled to 1.5° C. during 5 hours and stirredfor 12 hours at this temperature. The solid was filtered on Büchnerfilter and conditioned on the filter with vacuum for 40 minutes. The wetproduct (817 g) was dried in vacuum oven to constant weight.

For the first 13 hours, the material was dried at 30° C. and 35-27 mbar,then for an additional 7 hours at 40° C. and 30-18 mbar to produce a dryproduct (771.2 g, Yield 94.6%)—white crystalline powder (Batch “90” inTables 8-9; sample 3)

Dry detomidine HCl monohydrate was analyzed for water by CKF (H₂O=7.37%)and for purity by HPLC, the results presented in Table 14. The physicalcharacterization results are shown in Table 10 above.

The material was subjected to physical characterization and microscopicobservation for particle morphology (regular prisms) microscopicphotograph presented in FIG. 7.

TABLE 14 Properties of detomidine HCl (sample 3) Before Monohydrateafter re-crystallization crystallization Color Non GMP, white WhiteImpurities by HPLC, % area RRT = 0.20-0.21% area ND 0.03 Impurity A (RRT= 0.33% area) 0.15 0.03 KKT = 0.48¹% area 0.01 ND RRT = 0.61¹% area NDND iso-detomidine (RRT = 1.14% 0.02 ND area) Total Impurities 0.19 0.06¹system peak

Example 6: Synthesis of Iso-Detomidine

Scheme 1 outlines a process for the synthesis of iso-detomidine wasdeveloped to produce a solid iso-detomidine HCl in high yield andsubstantially free of impurities.

Example 6a: Sandmeyer Reaction

3,4 dimethyl aniline (150 g, 1.24M) was mixed with acetonitrile (0.6liter) in a 5 liter flask, chilled to 10° C. and water (1.2 liter) addeddropwise over 5 minutes. The mixture was cooled to 5° C. withice-ethanol bath and concentrated H₂SO₄ (98% wt., 363 g 3.71M) was addeddropwise over 30 min at 5-10° C.

Sodium nitrite (NaNO₂) aqueous solution (89.7 g in 300 ml water, 1.30M)was then added dropwise over 30 min at 0-5° C. to give a brown solution.The resulting solution of diazonium salt was stirred at 0-5° C. for anadditional 30 min.

In another 5 liter flask KI (225 g, 1.36M) was dissolved in water (0.8liter) during stirring and cooled. The diazonium salt solution was addeddropwise to the KI solution at 7-13° C. during 35 min, the batch stirredat 7-13° C. for 1.25 hr to give a black solution. MTBE (2.0 liter) wasthen added to the reaction mixture and Na₂SO₄ (23.4 g) was introduced insmall portions during 5 min.

The mixture was settled and the organic phase separated and washed withtwo portions of brine (2×500 ml). The organic solution was concentratedunder vacuum to a volume of about 250 ml. The product was purified byvacuum distillation at ca. 40 Pa, BP=52-60° C. to give 246 g ofintermediate 1 as a brown oil with a product yield of 86%.

Example 6b: TRT Protection Reaction

1H-Imidazole-4-carbaldehyde (45.2 g, 0.47M) and acetonitrile (0.8 liter)are introduced into a 2 liter flack and cooled to 8° C., then TRT-Cl(131.0 g, 0.47M) was added at 8° C. and TEA (57.1 g, 0.56M) was addeddropwise during 20 min. The reaction mixture was stirred at 8 to 18° C.for 2 hrs.

The reaction mixture was poured into a stirring mixture of water (0.72liter) and MTBE (0.72 liter) and stirred for 10 minutes. The resultingsolid was isolated by filtration on Büchner funnel and dissolved withTHF (3 liter). The solution was dried over Na₂SO₄ and concentrated toremove most of the solvent.

MTBE (400 ml) and PE (200 ml) was added to the residue, the mixturestirred at 8° C. for 16 hrs. The precipitated solid was isolated byfiltration on Büchner filter and dried in air for 16 hrs at roomtemperature. Then the filter cake is dried by azeotropic drying with2-Me-THF (2×500 ml) to give 129 g of intermediate 2 as white solid witha yield of 66.5%.

Example 6c: Grignard Reaction

A 2M solution of i-PrMgCl in THF (0.275 liter, 0.55M) and THF (1.0liter) was introduced to a 2 liter flask at 12° C. Intermediate 1 (121.8g, 0.525M) was added dropwise during 20 min. The mixture was stirred at12-15° C. for 3 hrs.

Intermediate 2 (84.6 g, 0.25M) was added in small portions withoutcooling during 30 min, with a temperature rise to 25° C., to give alight brown solution. The solution was stirred for 2.5 hrs at 15° C. andadded to aqueous solution of NH₄Cl (117 g in 0.7 liter water) during 10min at 5° C. PE (1.6 liter) was added during 5 min and the mixturestirred for extra 25 min.

Precipitated solid filtered on Büchner funnel and then re-slurred withmixture of MTBE (400 ml), water (600 ml) and PE (200 ml). Then the solidwas filtered on Büchner funnel and re-slurred with MeOH (700 ml) at 60°C. for 10 min, cooled to 20° C. with cold water bath and filtered againon Büchner funnel. The solid product was dried in an air oven at 45° C.for 2 hrs to give 112 g of intermediate 3 as a white solid with a yieldof 89.9%.

Example 6d: Reductive Dehydroxylation and De-Protection

Intermediate 3 (107 g, 0.240M) and DCM (1.10 liter) were introduced to a2 liter flask at 11° C., TFA (214 ml) was added dropwise over 5 minswith a temperature rise to 14° C.

The mixture was stirred for about 5 mins and Et₃SiH (94.4 g, 0.794M)added dropwise during 5 mins. After stirring at 25-30° C. for 16 hrs themixture was concentrated by rotary evaporation at 40° C. to a residue.

The residue of evaporation was dissolved in DCM (600 ml) and washed with1.5M aq. HCl (0.24 liter). Organic phase was separated and washed withaq. NaOH (11.5 g in 200 ml water), pH of aqueous phase 13. Two phaseswere separated and the organic phase washed with brine (200 ml) driedover Na₂SO₄ and filtered. The resulting solution was concentrated byrotary evaporation.

The evaporation residue was dissolved in mixture of EtOAc (500 ml) andEtOH (30 ml) and then 4M HCl solution in dioxane (40 ml) was addeddropwise in 5 minutes, pH=1-2 adjusted and a white solid precipitatedout.

The solid product was filtered on Büchner funnel, the cake dried in airfor 16 hrs to give 36 g of white solid.

The solid product was re-crystallized from iPrOH/Acetone. The dry cake(36 g) and iPrOH were introduced into a 1 liter flask and heated todissolution. Acetone (360 ml) was added to the resulting colorlesssolution at reflux during 10 mins. The mixture was cooled to 8° C. andstirred at this temperature for additional 4.5 hrs. The solid productwas filtered on Büchner funnel and dried in air for 36 hrs. 29.2 g ofiso-detomidine as a white solid was obtained with a yield of 54.4%. The¹H-NMR spectra of iso-detomidine is shown in FIG. 15.

Example 7: Re-Crystallization of Detomidine HCl Spiked with 2%Iso-Detomidine

Detomidine HCl monohydrate (26.0 g), iso-detomidine HCl (0.52 g) anddeionized water (68.7 g) were introduced to a 100 ml glass jacketedreactor equipped with a mechanical stirrer, a thermocouple and acirculating oil bath for heating and cooling. The batch was stirred andheated to 51° C., at 47° C. complete dissolution was observed.

The solution was cooled gradually and at 42° C. seeded with detomidineHCl monohydrate. Crystallization initiation was observed at 39° C. andthen the batch was cooled to 3° C. for 5 hours, filtered on Büchnerfilter and conditioned on the filter with vacuum. The wet product (20.7g) was dried in vacuum oven to constant weight to produce a dry product(20.13 g, Yield 75.9%)—white crystalline powder

Dry detomidine HCl monohydrate was analyzed for PSD and morphology, theresults are presented in Table 8 (Sample. No. 91). The purity ofre-crystallized material was analyzed using the optimized HPLC processdisclosed herein, and the results are presented in Table 15.

TABLE 15 Properties of detomidine HCl following recrystallization fromiso-detomidine spiked material Before After purification purificationColor White White Impurities by HPLC, % area Impurity A (RRT = 0.33)^(a)0.05 0.01 RRT = 0.46-0.48 ND 0.03 iso-detomidine HCl 2.17^(b) 0.08 (RRT= 1.14) Total Impurities 2.23 0.11 ^(a)area % ^(b)Spiked amount,calculated

Example 8: Properties of Solid Form Detomidine Base Example 8a: X-RayPowder Diffraction (XRPD) Kα1Mode

XRPD patterns were recorded on a PANalytical X Pert Pro diffractometerequipped with an Xcelerator detector using Cu Kα radiation at 45 kV and40 mA.

Kα1 radiation was obtained with a highly oriented crystal (Ge111)incident beam monochromator. A 10 mm beam mask, and divergence)(¼°, andanti-scatter)(⅛° slits were inserted on the incident beam side.Receiving (5 mm) and Soller (0.04 rad.) slits were inserted on thediffracted beam side. The XRPD scan was collected from ca. 2 to 40° 2θwith a 0.0080° step size and 96.06 sec counting time which resulted in ascan rate of approximately 0.5°/min. The sample was spread on a glassplate or a silicon zero background (ZBG) plate for the measurement. Thesample was rotated at 15 revolutions/min on a PANalytical PW3065/12Spinner. Measurement of the Si reference standard before the datacollection resulted in values for 20 and intensity that were well withinthe tolerances of 28.38<20<28.50 and significantly greater than theminimum peak height of 150 cps.

Example 8b: XRPD Standard Mode

XRPD patterns were recorded on a PANalytical X Pert Pro diffractometerequipped with an X celerator detector using Ni filtered Cu Kα radiationat 45 kV and 40 mA. A 10 mm beam mask, and divergence)(¼° andanti-scatter (⅛°), and Soller (0.04 rad.) slits were inserted on theincident beam side. Receiving (5 mm) and Soller (0.04 rad.) slits and aNi filter were inserted on the diffracted beam side. The X-ray powderpattern scan was collected from ca. 2 to 40° 2θ with a 0.0080° step sizeand 96.06 sec counting time which resulted in a scan rate ofapproximately 0.5°/min. The sample was spread on a glass plate or asilicon zero background (ZBG) plate for the measurement. The sample wasrotated at 15 revolutions/min on a PANalytical PW3065/12 Spinner.Measurement of the Si reference standard before the data collectionresulted in values for 20 and intensity that were well within thetolerances of 28.38<2θ<28.50 and significantly greater than the minimumpeak height of 1000 cps. The XRPD pattern of detomidine free base isshown in FIG. 16.

Example 8c: DSC—Differential Scanning Calorimetry

Thermal curves were acquired using a TA Discovery DSC unit. Solidsamples of 5-20 mg were weighed into Tzero™ aluminum pinholehermetically sealed pin hole pans. The DSC cell was then purged withnitrogen and the temperature heated at 10° C./min. from 0° to 200° C.Indium (Tm=156.6° C.; ΔHFus=28.45 J g-1) was used for calibration. TheDSC thermogram of detomidine free base is shown in FIG. 17.

Example 8d: TGA—Thermogravimetric Analyzer

Thermal curves were acquired using a Perkin-Elmer Pyris 1 TGA unitrunning Pyris software version 6.0 calibrated with alumel (95% nickel,2% manganese, 2% aluminum and 1% silicon), nickel and calcium oxalatemonohydrate. TGA samples between 1-10 mg were monitored for percentweight loss as heated from 25 to 250° C. at 10° C./min in a furnacepurged with Helium at ca. 50 mL/min. The percent weight loss to 150° C.is the value reported in Table 16 and the TGA thermogram of detomidinefree base in FIG. 18.

Table 16 shows the first “25” peaks identified in an automatic peaksearch Pos. Height FWHM Left d-spacing Rel. Int. [°2θ] [cts] [°2θ] [Å][%] 9.4369 6143.66 0.0708 9.37201 10.89 10.2822 1613.51 0.0787 8.603362.86 13.1267 19079.67 0.1023 6.74475 33.81 16.4182 11003.25 0.10235.39925 19.50 16.8720 1313.14 0.0945 5.25502 2.33 18.1807 56437.430.1496 4.87959 100.00 18.8002 38924.53 0.0866 4.72018 68.97 18.903743045.45 0.0866 4.69456 76.27 20.5659 12491.60 0.0787 4.31875 22.1321.0058 9893.49 0.0866 4.22929 17.53 21.2170 19555.98 0.0864 4.1841934.65 21.2634 12727.98 0.0384 4.18555 22.55 23.1638 12929.43 0.17283.83676 22.91 24.1591 9445.17 0.0960 3.68089 16.74 24.2191 6714.470.0384 3.68103 11.90 24.6326 16859.78 0.1632 3.61120 29.87 25.42405466.94 0.1056 3.50055 9.69 25.9866 26594.20 0.1056 3.42603 47.1226.0536 17505.31 0.0384 3.42587 31.02 26.4132 1532.75 0.0576 3.371652.72 28.1107 7071.67 0.1248 3.17180 12.53 28.5554 17443.62 0.10563.12340 30.91 29.1749 265.43 0.1536 3.05848 0.47 30.0116 2373.54 0.09602.97508 4.21 30.8465 598.97 0.1152 2.89644 1.06

1. Detomidine or a pharmaceutically acceptable salt thereof, thecompound substantially free of iso-detomidine.
 2. The detomidine ofclaim 1, wherein the pharmaceutically acceptable salt of detomidine isdetomidine HCl.
 3. The detomidine of claim 2, wherein the detomidine HClis the monohydrate form.
 4. The detomidine of claim 2, wherein thedetomidine HCl is the anhydrous form.
 5. The detomidine any one ofclaims 1-4, wherein the total amount of impurities is not more than 0.1%area, not more than 0.06% area, or not more than 0.02% area, based onHPLC.
 6. The detomidine of any one of claims 1-5, wherein the totalamount of impurities is not more than 0.06% area, based on HPLC.
 7. Thedetomidine of any one of claims 1-6, wherein the detomidine or apharmaceutically acceptable salt thereof is further substantially freeof iso-impurity A(((RS)-(3,4-dimethylphenyl)(1H-imidazol-4-yl)methanol)) and/or impurityA ((RS)-(2,3-dimethylphenyl)(1H-imidazol-4-yl)methanol) and/or(2,3-dimethylphenyl)(1H-imidazol-4-yl) methanone.
 8. Detomidine or apharmaceutically acceptable salt thereof, the compound substantiallyfree of iso-detomidine and iso-impurity A(((RS)-(3,4-dimethylphenyl)(1H-imidazol-4-yl)methanol)).
 9. Detomidineor a pharmaceutically acceptable salt thereof, the compoundsubstantially free of iso-detomidine and(2,3-dimethylphenyl)(1H-imidazol-4-yl) methanone.
 10. Detomidine or apharmaceutically acceptable salt thereof, the compound substantiallyfree of iso-detomidine, iso-impurity A(((RS)-(3,4-dimethylphenyl)(1H-imidazol-4-yl)methanol)) and(2,3-dimethylphenyl)(1H-imidazol-4-yl) methanone.
 11. The detomidine ofany one of claims 1-6 and 8-10, wherein the detomidine or apharmaceutically acceptable salt thereof is further substantially freeof impurity A ((RS)-(2,3-dimethylphenyl)(1H-imidazol-4-yl)methanol). 12.The detomidine of any one of claims 1-11, wherein the detomidine or apharmaceutically acceptable salt thereof is further substantially freeof impurity B((RS)-(1-benzyl-1H-imidazol-5-yl)(2,3-dimethylphenyl)methanol) and/orimpurity C (4-[(2,3-dimethylcyclohexyl)methyl]-1H-imidazole).
 13. Acomposition comprising the detomidine of any one of claims 1-12, and avehicle.
 14. A pharmaceutical composition comprising detomidine or apharmaceutically acceptable salt thereof substantially free ofiso-detomidine; and a pharmaceutically acceptable carrier.
 15. Thepharmaceutical composition of claim 14, wherein the pharmaceuticallyacceptable salt of detomidine is detomidine HCl.
 16. The pharmaceuticalcomposition of claim 15, wherein the detomidine HCl is the monohydrateform.
 17. The pharmaceutical composition of claim 15, wherein thedetomidine HCl is the anhydrous form.
 18. The pharmaceutical compositionof any one of claims 14-17, wherein the total amount of impurities isnot more than 0.1% area, not more than 0.06% area, or not more than0.02% area, based on HPLC.
 19. The pharmaceutical composition of any oneof claims 14-17, wherein the total amount of impurities is not more than0.06% area, based on HPLC.
 20. The pharmaceutical composition of any oneof claims 14-19, further substantially free of iso-impurity A(((RS)-(3,4-dimethylphenyl)(1H-imidazol-4-yl)methanol)).
 21. Thepharmaceutical composition of any one of claims 14-20, furthersubstantially free of (2,3-dimethylphenyl)(1H-imidazol-4-yl) methanone.22. A pharmaceutical composition comprising detomidine or apharmaceutically acceptable salt thereof substantially free ofiso-detomidine, iso-impurity A(((RS)-(3,4-dimethylphenyl)(1H-imidazol-4-yl)methanol)) and(2,3-dimethylphenyl)(1H-imidazol-4-yl) methanone; and a pharmaceuticallyacceptable carrier.
 23. A pharmaceutical composition comprisingdetomidine or a pharmaceutically acceptable salt thereof substantiallyfree of iso-detomidine and iso-impurity A(((RS)-(3,4-dimethylphenyl)(1H-imidazol-4-yl)methanol)); and apharmaceutically acceptable carrier.
 24. A pharmaceutical compositioncomprising detomidine or a pharmaceutically acceptable salt thereofsubstantially free of iso-detomidine and(2,3-dimethylphenyl)(1H-imidazol-4-yl) methanone; and a pharmaceuticallyacceptable carrier.
 25. The pharmaceutical composition of any one ofclaims 13-24, further substantially free of impurity A((RS)-(2,3-dimethylphenyl)(1H-imidazol-4-yl)methanol).
 26. Thepharmaceutical composition of any one of claims 13-25, furthersubstantially free of impurity B((RS)-(1-benzyl-1H-imidazol-5-yl)(2,3-dimethylphenyl)methanol) and/orimpurity C (4-[(2,3-dimethylcyclohexyl)methyl]-1H-imidazole).
 27. Aprocess for the preparation of a monohydrate form of detomidine HClsubstantially free of iso-detomidine comprising a. crystallizing amonohydrate form of detomidine HCl from an aqueous solution of ananhydrous form of detomidine HCl which comprises iso-detomidine; whereinthe crystallization takes place by cooling the aqueous solution to atemperature of from about 0° C. to 31° C., optionally in the presence ofsolid detomidine base or detomidine HCl, until a slurry is formed, andb. collecting the monohydrate form of detomidine HCl substantially freeof iso-detomidine.
 28. A process for the preparation of a monohydrateform of detomidine HCl substantially free of iso-detomidine comprisinga. treating an aqueous solution of an anhydrous form of detomidine HClwhich comprises iso-detomidine with active carbon; b. converting thedetomidine HCl to detomidine base to form an aqueous solution ofdetomidine base; c. crystallizing the monohydrate form of detomidine HClfrom the aqueous solution of detomidine base by adding a sufficientamount of HCl, wherein the crystallization takes place by cooling theaqueous solution to between about 3° C. and 37° C., optionally in thepresence of solid detomidine HCl, until a slurry is formed, and d.collecting the monohydrate form of detomidine HCl substantially free ofiso-detomidine.
 29. The process of claim 27 or 28, wherein theHCl:detomidine base ratio (mole:mole) is about 1 to about 1.5.
 30. Theprocess of claim 29, wherein the HCl:detomidine base ratio (mole:mole)is about 1.5.
 31. The process of any one of claims 27-30, wherein thewater:detomidine (V/wt) HCl ratio is about 2-3.
 32. The process of anyone of claims 27-31, wherein the crystallization of the monohydrate formof detomidine HCl from an aqueous solution occurs at a dissolutiontemperature of between about 35° C.-50° C.
 33. The process of any one ofclaims 27-32, wherein the crystallization initiation temperature isabout 30° C.-45° C.
 34. The process of any one of claims 27-33, whereinthe monohydrate form of detomidine HCl has a mean crystal size of 0.3 to0.7 mm.
 35. The process of claim 34, wherein the shape of the crystalsof the monohydrate form of detomidine HCl is rod like and/or prism like.36. The process of any of claims 27-35 wherein the monohydrate form ofdetomidine HCl has a water content of about 7.5% as determined by KarlFisher analysis.
 37. The monohydrate form of detomidine HCl obtained bya process of any one of claims 24-33.
 38. A composition comprising themonohydrate form of detomidine HCl obtained by a process of any one ofclaims 27-36; and a vehicle.
 39. A pharmaceutical composition comprisingthe monohydrate form of detomidine HCl obtained by a process of any oneof claims 27-36; and a pharmaceutically acceptable carrier
 40. A methodof treating a human subject in need thereof, comprising administering tothe human subject the pharmaceutical composition of any one of claims14-26 and
 39. 41. The method of claim 40, wherein the human subject isin need of an analgesic.
 42. A process for validating a batch of amonohydrate form of detomidine HCl drug substance, comprising a.determining the amount of iso-detomidine in a sample of the batch, andb. validating the batch for distribution only if the sample of the batchcontains not more than 0.01% area of of iso-detomidine and/oriso-impurity A relative to detomidine.
 43. The detomidine of claim 1,which is detomidine free base.
 44. The detomidine free base of claim 43,having 2 theta values comprising at least one of the values as shown inTable 16, herein.